代谢型谷氨酸受体5的6-（嘧啶-5-基甲基）喹啉-8-甲酰胺负变构调节剂的发现。
Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.
作者信息
Felts Andrew S, Rodriguez Alice L, Morrison Ryan D, Blobaum Anna L, Byers Frank W, Daniels J Scott, Niswender Colleen M, Conn P Jeffrey, Lindsley Craig W, Emmitte Kyle A
机构信息
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2018 Jun 1;28(10):1679-1685. doi: 10.1016/j.bmcl.2018.04.053. Epub 2018 Apr 22.
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
基于之前的工作，即已确定稠合杂环可作为我们的亲代谢型谷氨酸受体（mGlu）负变构调节剂（NAMs）先导系列中吡啶甲酰胺核心的可行替代物，我们设计了一系列新型的6-(嘧啶-5-基甲基)喹啉-8-甲酰胺mGlu NAMs。这些新的喹啉衍生物还含有碳连接基，以取代我们之前发表的化学类型中常见的二芳基醚氧原子。在基于细胞的功能性mGlu测定中对化合物进行了评估，一个示例性类似物27相对于其他七种mGlu受体具有>60倍的选择性。还在大鼠和人肝S9组分的代谢稳定性测定中研究了选定的化合物，它们表现出细胞色素P450介导和非细胞色素P450介导的混合代谢。
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